High HbA1c and Hypoglycemia Associated with Diabetic Retinopathy Onset and Progression

Higher HbA1c and nonsevere hypoglycemia are associated with a higher risk of onset of diabetic retinopathy (DR) in patients with type 2 diabetes (T2D), even after achieving good glycemic management with a very low incidence of severe hypoglycemia. This indicates the importance of strict glycemic management.1

Acute improvements in glycemia management have been shown to result in preexisting DR progression, and severe hypoglycemia was reported in previous research to elevate DR onset risk. However, while intensive therapy showed a frequent association with severe hypoglycemia in previous trials, sufficient glycemic management was not achieved in many of them. Therefore the relationship between glycemic management and retinopathy in patients without severe hypoglycemia remains to be fully studied.1

“Here, we describe a secondary analysis of retinopathy events as a prespecified secondary outcome in the J-DOIT3 study,” Takayoshi Sasako, MD, PhD, department of diabetes and metabolic diseases, Graduate School of Medicine, the University of Tokyo, and colleagues wrote. “We examined the effects of not only intensified multifactorial intervention, but also each component of treatment (e.g., glycemic management) and hypoglycemia on the onset of progression of retinopathy.”1

The J-DOIT3 trial was a multicenter, open-label, parallel-group randomized clinical trial broken into an intervention study and a follow-up study. It investigated the efficacy of an intensified multifactorial intervention on cardiovascular outcomes and mortality in T2D. The primary endpoint measure was occurrence of myocardial infarction, coronary bypass surgery, percutaneous transluminal coronary angioplasty, stroke, carotid endarterectomy, percutaneous transluminal cerebral angioplasty, carotid artery stenting, or death.1,2

To be eligible for inclusion, patients had to be between 45-70 years old at study entry and have T2D. Additionally, included patients exhibited hypertension and/or dyslipidemia with an HbA1c ≥6.9%. Patients with poorly controlled hypertension despite pharmacological therapy, those on insulin therapy, those with non-diabetic renal disease, those with type 1 and other diabetes due to pathogenic mechanisms other than those associated with T2D, and those who tested anti-GAD antibody positive, among other conditions, were excluded.2

A total of 2540 participants (5080 eyes) were enrolled in the trial; these patients were then randomly assigned in a 1:1 ratio to either conventional therapy or intensive therapy for stricter treatment targets, such as HbA1c <6.2%). Mean age was 59 years (standard deviation [SD] 6.3).1

Investigators noted 679 retinopathy events as time to first events during the intervention period – 317 occurred in the intensive therapy group and 362 in the conventional therapy group. After examining cumulative incidence, investigators saw an association between intensive therapy and a significant risk reduction in retinopathy events (hazard ratio [HR], 0.86; 95% CI, 0.74-0.998; P = .046).1

In a breakdown of the first retinopathy events, Sasako and colleagues found that 261 events in the intensive group and 311 in the conventional group were onset of retinopathy in patients without retinopathy at baseline. Intensive therapy was also associated with a risk reduction in onset (HR, 0.83; 95% CI, 0.7-0.98; P = .03). Of the remainder, 56 events in the intensive group and 51 in the conventional group were progression of retinopathy in participants with nonproliferative retinopathy in ≥1 eye at baseline, with intensive therapy associated with no risk reduction in progression (HR, 1.02; 95% CI, 0.7-1.49; P = .93).1

Cox regression was then performed to determine the effect of each component of treatment on onset of retinopathy. HbA1c at 1 year was associated with an increased risk of onset (HR, 1.31; 95% CI, 1.13-1.51; P <.001), but intensive therapy was not. Investigators believe that the risk reduction in onset observed with intensive therapy may be attributed to improvements in glycemic management during the intervention.1

Finally, investigators examined the association between yearly incidence of hypoglycemia and onset or progression of retinopathy. The risk of onset was found to be higher in those with ≤0.5 hypoglycemic episodes per year (HR, 1.25; 95% CI, 1.02-1.53) and even higher in those with >1 episode annually (HR, 1.85l 95% CI, 1.39-2.47) (P for trend <.001). However, yearly hypoglycemia incidence was not significantly associated with progression. After further stratification by treatment group, these results were similar.1

“Taken together, it is vitally important to achieve strict and yet safe glycemic management in treating people with type 2 diabetes,” Sasako and colleagues wrote. “The HbA1c target should be individualized, but glycemic management with an HbA1c target of 7% or lower may be recommended in a certain proportion of people with type 2 diabetes. So-called newer classes of antidiabetic drugs are expected to help clinicians achieve strict and safe glycemic management.”1

References

1. Sasako T, Ueki K, Miyoshi K, et al. Effect of a Multifactorial Intervention on Retinopathy in People With Type 2 Diabetes: A Secondary Analysis of the J-DOIT3 Randomized Clinical Trial. JAMA Ophthalmol. Published online October 23, 2025. doi:10.1001/jamaophthalmol.2025.3819

2. Japan Foundation for the Promotion of International Medical Research Cooperation. The Japan Diabetes Optimal Integrated Treatment Study for 3 Major Risk Factors of Cardiovascular Diseases (J-DOIT3). ClinicalTrials.gov identifier: NCT00300976. Updated August 3, 2017. Accessed October 30, 2025. https://www.clinicaltrials.gov/study/NCT00300976?cond=NCT00300976&rank=1